DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 696

cells. In another study, Hu et al. 172 reported that BITC and PEITC were able to deplete
cellular concentrations of glutathione (GSH) in Panc-1 and Caco-2 cells after 2- and
24-hour ITC treatments. However, no significant changes in glutathione- S -transferase
activity were found in the presence of BITC, PEITC, or NITC. In addition, PEITC
and/or its metabolites was shown to be transported by MRP1 and MRP2 but not
by Pgp. 172 , 173 These results indicate that certain dietary ITCs inhibit the Pgp- and
MRP1-mediated efflux of anticancer drugs in MDR cancer cells, and the interactions
probably involve multiple mechanisms.
In a recent study, the effects of 12 ITCs on the cellular accumulation of mitox-
antrone (MX) were measured in BCRP-overexpressing human breast cancer (MCF-7)
and large cell lung carcinoma (NCI-H460) cells. At a concentration of 10 or 30 M,

seven ITCs increased MX accumulation significantly in both cell lines and reversed
MX cytotoxicity, indicating that ITCs could also modulate BCRP activities. 174

22.3. CONCLUSIONS

In recent years, a wealth of evidence has been generated from in vitro and in vivo
studies showing that many diets and nutrients interact extensively with drug trans-
porters and play critical roles in multidrug resistance reversal and drug disposition.
The importance of transporter-mediated diet-drug interactions has been recognized
increasingly and reported in a number of preclinical and clinical studies. Some nutri-
ents rich in fruits and vegetables, such as flavonoids and isothiocyanates, have been
identified as potent inhibitors or inducers of major efflux or uptake transporters. The
structural preferences of flavonoids for some efflux transporters have been described
in several structure-activity relationship studies. However, diet and nutrient interac-
tions with drug transporters still remain largely unknown. Most in vivo interaction
studies reported to date are focused primarily on the interactions between dietary sup-
plements and Pgp. Given the facts that MRPs and BCRP, and OATP are also essential
in drug disposition, it is important to appreciate pharmacokinetic interactions of diet
and nutrients with these transporters. The concentrations of many flavonoids required
to produce significant modulation on activities of these transporters appear to be, in
general, within the micromolar range, which is achievable in the intestine after intake
of food and especially, dietary supplements. Therefore, altered disposition of MRP,
BCRP, and OATP substrates following ingestion of a regular diet is likely to occur
and needs further characterization. Moreover, structure-activity relationship (QSAR)
studies will be crucial to better understand the potential of dietary components for in-
hibiting or inducing drug transport and the potential for significant in vivo diet/dietary
supplement-drug interactions.

REFERENCES

1. Singh BN. 1999. Effects of food on clinical pharmacokinetics. Clin Pharmacokinet
37(3):213-255.